In immunocompetent individuals, non-typhoidal Salmonella serotypes (NTS) are associated with gastroenteritis, a localized infection with low mortality manifesting as diarrhea, vomiting and intestinal cramping. However, a breach of mucosal barrier functions in immunocompromised individuals can result in the development of a life threatening bacteremia. There is currently an epidemic of disseminated NTS infections in sub-Saharan Africa, which are associated with bacteremia, meningitis and sepsis, and often have a fatal outcome. Epidemiological associations suggest that severe malaria in young children is an important immunocompromising condition predisposing to NTS bacteremia. In particular, the prevalence of disseminated NTS infections in children with Plasmodium falciparum malaria is striking. However the precise immune defect caused by severe malaria, which puts patients at an increased risk of developing NTS bacteremia, has not been identified. The objective of this application is to use a recently developed co-infection model of malaria and NTS to identify effects of malaria on the immune response to a subsequent bacterial infection. Our central hypothesis is that in pediatric patients, underlying malaria infection leads to both a breach in intestinal barrier function and a reduced ability to check growth at systemic sites by interfering with neutrophil recruitment and bacteriocidal activity. Defining the basis for increased susceptibility to disseminated infection will lead to a better understanding of the immune mechanisms that help to confine NTS to the GI tract of the healthy host. The fact that NTS/malaria co-infections are understudied, even though they represent a major cause of mortality in sub-Saharan Africa, makes the proposed work highly significant. It is our expectation that the proposed research will provide important new insights into specific immune mechanisms that are important for mucosal barrier function to NTS infection. The outcome of the proposed research is likely to provide novel paradigms of how polymicrobial infections affect disease outcome. PUBLIC HEALTH RELEVANCE: Nontyphoidal Salmonella serotypes (NTS), which usually cause diarrheal disease in immunocompetent individuals, are a leading cause of bacteremia in immunocompromised individuals in Sub-Saharan Africa. Severe malarial anemia is a major risk factor in African children for dissemination of NTS from the intestine to the bloodstream. We expect our proposed research to identify the immune defects in pediatric malaria patients predisposing them to NTS bacteremia will provide important new insights into specific immune mechanisms that are important for maintaining the intestinal barrier function to bacteria and broaden our understanding of how simultaneous infection with multiple pathogens affect disease outcome.